FK 506 improves function of muscles reinnervated by embryonic neurons placed in peripheral nerve

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Abstract from Neuroscience. 2005;130(3):619-30

The immunophilin ligand FK506, but not the P38 kinase inhibitor SB203580,

improves function of adult rat muscle reinnervated from transplants of embryonic

neurons.

Grumbles RM, Casella GT, Rudinsky MJ, Godfrey S, Wood PM, CK.

The Miami Project to Cure Paralysis, Department of Neurological Surgery,

University of Miami School of Medicine, Lois Pope Life Center, 1095 NW 14(th)

Terrace (R48), Miami, FL 33136 USA.

Injury to the adult CNS often involves death of motoneurons, resulting in the

paralysis and progressive atrophy of muscle. There is no effective therapy to

replace motoneurons in the CNS. Our strategy to replace neurons and to rescue

denervated muscles is to transplant dissociated embryonic day 14-15 (E14-15)

ventral spinal cord cells into the distal stump of a peripheral nerve near the

denervated muscles. Here, we test whether long-term delivery of two

pharmacological inhibitors to denervated muscle, FK506 or SB203580, enhances

reinnervation of muscle from embryonic cells transplanted in the tibial nerve of

adult Fischer rats. FK506, SB203580 (2.5 mg/kg) or saline was delivered under

the fascia of the medial gastrocnemius muscle for 4 weeks, beginning when

muscles were denervated by section of the sciatic nerve.

After 1 week of nerve degeneration, one million E14-15 ventral spinal cord cells

were transplanted into the distal tibial nerve stump of each rat in the three

treatment groups. Ten weeks later, all cell transplants had neuron-specific

nuclear protein (NeuN) positive neurons. Neuron survival and axon regeneration

were similar across treatments. An average (+/-S.E.) of 210+/-66, 100+/-36 and

176+/-58 myelinated axons grew distally from the cell transplants of rats with

muscles treated with FK506, SB203580 or saline, respectively. Regenerating axons

in muscles of all three treatments groups were detected with antibodies against

phosphorylated neurofilaments and synaptophysin, and motor end plates were

labeled with alpha-bungarotoxin. Muscles of rats that received transplants of

media only had no axon growth, indicating that the muscles were denervated. The

mean muscle fiber areas of rats that received cell transplants and had long-term

delivery of FK506, SB203580 or saline to muscles were significantly larger than

those of denervated muscle fibers.

Thus, cell transplantation reduced muscle atrophy. Transplantation of embryonic

cells also resulted in functional muscle reinnervation. Electromyographic

activity and force were evoked from >90% of the muscles of rats with cell

transplants, but not from denervated muscles.

FK506-treated muscles were significantly more fatigue resistant than naive

control muscles. FK506-treated muscles also had significantly stronger motor

units than those in SB203580 or saline-treated muscles. These data suggest that

a pathway regulated by FK506 improves the function of muscles reinnervated by

embryonic neurons placed in peripheral nerve.